Alleviating Pyroptosis of Intestinal Epithelial Cells to Restore Mucosal Integrity in Ulcerative Colitis by Targeting Delivery of 4-Octyl-Itaconate.

Current therapies primarily targeting inflammation often fail to address the root relationship between intestinal mucosal integrity and the resulting dysregulated cell death and ensuing inflammation in ulcerative colitis (UC). First, UC tissues from human and mice models in this article both emphasize the crucial role of Gasdermin E (GSDME)-mediated pyroptosis in intestinal epithelial cells (IECs) as it contributes to colitis by releasing proinflammatory cytokines, thereby compromising the intestinal barrier. Then, 4-octyl-itaconate (4-OI), exhibiting potential for anti-inflammatory activity in inhibiting pyroptosis, was encapsulated by butyrate-modified liposome (4-OI/BLipo) to target delivery for IECs. In brief, 4-OI/BLipo exhibited preferential accumulation in inflamed colonic epithelium, attributed to over 95% of butyrate being produced and absorbed in the colon. As expected, epithelium barriers were restored significantly by alleviating GSDME-mediated pyroptosis in colitis. Accordingly, the permeability of IECs was restored, and the resulting inflammation, mucosal epithelium, and balance of gut flora were reprogrammed, which offers a hopeful approach to the effective management of UC.

Lipid Metabolism-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Advanced Gastric Cancer.

Objective: Abnormal lipid metabolism is known to influence the malignant behavior of gastric cancer. However, the underlying mechanism remains elusive. In this study, we comprehensively analyzed the biological significance of genes involved in lipid metabolism in advanced gastric cancer (AGC). Methods: We obtained gene expression profiles from The Cancer Genome Atlas (TCGA) database for early and advanced gastric cancer samples and performed differential expression analysis to identify specific lipid metabolism-related genes in AGC. We then used consensus cluster analysis to classify AGC patients into molecular subtypes based on lipid metabolism and constructed a diagnostic model using least absolute shrinkage and selection operator- (LASSO-) Cox regression analysis and Gene Set Enrichment Analysis (GSEA). We evaluated the discriminative ability and clinical significance of the model using the Kaplan-Meier (KM) curve, ROC curve, DCA curve, and nomogram. We also estimated immune levels based on immune microenvironment expression, immune checkpoints, and immune cell infiltration and obtained hub genes by weighted gene co-expression network analysis (WGCNA) of differential genes from the two molecular subtypes. Results: We identified 6 lipid metabolism genes that were associated with the prognosis of AGC and used consistent clustering to classify AGC patients into two subgroups with significantly different overall survival and immune microenvironment. Our risk model successfully classified patients in the training and validation sets into high-risk and low-risk groups. The high-risk score predicted poor prognosis and indicated low degree of immune infiltration. Subgroup analysis showed that the risk model was an independent predictor of prognosis in AGC. Furthermore, our results indicated that most chemotherapeutic agents are more effective for AGC patients in the low-risk group than in the high-risk group, and risk scores for AGC are strongly correlated with drug sensitivity. Finally, we performed qRT-PCR experiments to verify the relevant results. Conclusion: Our findings suggest that lipid metabolism-related genes play an important role in predicting the prognosis of AGC and regulating immune invasion. These results have important implications for the development of targeted therapies for AGC patients.